Obstetric and Perinatal Pharmacology

I. Physiological Background for Pregnant

Introduction Physiological and anatomical alterations develop in many organ systems during the course of pregnancy and delivery. Early changes are due, in part, to the metabolic demands brought on by the fetus, placenta and uterus and, in part, to the increasing levels of pregnancy hormones, particularly those of progesterone and estrogen. Later changes, starting in mid-pregnancy, are anatomical in nature and are caused by mechanical pressure from the expanding uterus. These alterations create unique requirements for the pharmaceutical management of the pregnant woman. Cardiovascular System The pregnancy-induced changes in the cardiovascular system develop primarily to meet the increased metabolic demands of the mother and fetus. Blood Volume Blood Volume increases progressively from 6-8 weeks gestation (pregnancy) and reaches a maximum at approximately 32-34 weeks with little change thereafter. Most of the added volume of blood is accounted for by an increased capacity of the uterine, breast, renal, striated muscle and cutaneous vascular systems, with no evidence of circulatory overload in the healthy pregnant woman. The increase in plasma volume (40-50%) is relatively greater than that of red cell mass (20-30%) resulting in hemodilution and a decrease in hemoglobin concentration. Intake of supplemental iron and folic acid is necessary to restore hemoglobin levels to normal (12 g/dl). The increased blood volume serves two purposes. First, it facilitates maternal and fetal exchanges of respiratory gases, nutrients and metabolites. Second, it reduces the impact of maternal blood loss at delivery. Typical losses of 300-500 ml for vaginal births and 750-1000 ml for Caesarean sections are thus compensated with the so-called "autotransfusion" of blood from the contracting uterus. Blood Constituents Red cell mass is increased 20-30%. Since plasma volume increases early in pregnancy and faster than red blood cell volume, the hematocrit falls until the end of the second trimester, when the increase in the red blood cells is synchronized with the plasma volume increase. The hematocrit then stabilizes or may increase slightly near term. Leukocyte counts are variable during gestation, but usually remain within the upper limits of normal. Marked

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elevations, however, develop during and after parturition (delivery). Fibrinogen, as well as total body and plasma levels of factors VII, X and XII increases markedly. The number of platelets also rises, yet not above the upper limits of normal. Combined with a decrease in fibrinolytic activity, these changes tend to prevent excessive bleeding at delivery. The placenta may be partially responsible for this alteration in fibrinolytic status. Plasminogen levels increase concomitantly with fibrinogens levels, causing an equilibration of clotting and lysing activity. Thus, pregnancy is a relatively hypercoagulable state, but during pregnancy neither clotting nor bleeding times are abnormal. Cardiac Output Cardiac Output increases to a similar degree as the blood volume. During the first trimester cardiac output is 30-40% higher than in the nonpregnant state. Steady rises are shown on Doppler echocardiography, from an average of 6.7 liters/minute at 8-11 weeks to about 8.7 liters/minute flow at 36-39 weeks; they are due, primarily, to an increase in stroke volume (35%) and, to a lesser extent, to a more rapid heart rate (15%). There is a steady reduction in systemic vascular resistance (SVR) which contributes towards the hyperdynamic circulation observed in pregnancy. During labor, further increases are seen with pain in response to increased catecholamine secretion; this increase can be blunted with the institution of labor analgesia. Also during labor, there is an increase in intravascular volume by 300-500 ml of blood from the contracting uterus to the venous system. Following delivery this autotransfusion compensates for the blood losses and tends to further increase cardiac output by 50% of predelivery values. At this point, stroke volume is increased while heart rate is slowed. Cardiac Size/Position/ECG There are both size and position changes which can lead to changes in ECG appearance. The heart is enlarged by both chamber dilation and hypertrophy. Dilation across the tricuspid valve can initiate mild regurgitant flow causing a normal grade I or II systolic murmur. Upward displacement of the diaphragm by the enlarging uterus causes the heart to shift to the left and anteriorly, so that the apex beat is moved outward and upward. The size of the heart appears to increase by about 12%. These changes lead to common ECG findings of left axis deviation, sagging ST segments and frequently inversion or flattening of the T-wave in lead III. Blood Pressure
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Systemic arterial pressure is never increased during normal gestation. In fact, by midpregnancy, a slight decrease in diastolic pressure can be recognized. Pulmonary arterial pressure also maintains a constant level.

However, vascular tone is more dependent upon sympathetic control than in the nonpregnant state, so that hypotension develops more readily and more markedly consequent to sympathetic blockade following spinal or extradural anesthesia. Central venous and brachial venous pressures remain unchanged during pregnancy, but femoral venous pressure is progressively increased due to mechanical factors. Aortocaval Compression From mid-pregnancy, the enlarged uterus compresses both the inferior vena cava and the lower aorta when the patient lies supine. Obstruction of the inferior vena cava reduces venous return to the heart leading to a fall in cardiac output by as much as 24% towards term. In the unanaesthetised state, most women are capable of compensating for the resultant decrease in stroke volume by increasing systemic vascular resistance and heart rate. There are also alternative venous pathways, the paravertebral and azygos systems. During anesthesia, however, these compensatory mechanisms are reduced or abolished so that significant hypotension may rapidly develop. Obstruction of the lower aorta and its branches causes diminished blood flow to kidneys, uteroplacental unit and lower extremities. During the last trimester, maternal kidney function is markedly lower in the supine than in the lateral position. Furthermore, the fetus is compromised by insufficient transplacental gas exchange. Venous Distension Venous distension increases approximately to 150% during the course of gestation and the venous ends of capillaries become dilated, causing reduced blood flow. These vascular changes contribute to delayed absorption of subcutaneously or intramuscularly injected substances. Distension of the extradural veins heightens the risk of vascular damage during institution of a regional block. The increased venous volume within the rigid spinal canal reduces the volume or capacity of the extradural and intrathecal spaces for local anesthetic solutions. This will therefore increase the spread of injected drugs. Effects of the Labor on the Cardiovascular System When a patient is the supine position, uterine contractions can cause a 25% increase in maternal cardiac output, a 15% decrease in heart rate, and a resultant 33% increase in stroke volume. However when the laboring patient is in the later recumbent position, the hemodynamic parameters stabilize , with only a 7,6% increase in cardiac output, a 0,7% decrease in heart rate, and a 7,7% increase in stroke volume. These significant differences are attributable to inferior vena caval occlusion caused by the gravid uterus. During contractions, pulse pressure increases 26% in the supine position but only 6%

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in the lateral recumbent position. Central venous pressure increases in direct relationship to the intensity of uterine contraction and increased intraabdominal pressure. Additionally, cardiopulmonary blood volume increases 300-500mLduring contractions. At the time of delivery, hemodynamic alterations vary with the anesthetic used. Respiratory System Respiratory Tract Hormonal changes to the mucosal vasculature of the respiratory tract lead to capillary engorgement and swelling of the lining in the nose, oropharynx, larynx, and trachea. Symptoms of nasal congestion, voice change and upper respiratory tract infection may prevail throughout gestation. These symptoms can be exacerbated by fluid overload or edema associated with pregnancy-induced hypertension (PIH) or pre-eclampsia. In such cases, manipulation of the airway can result in profuse bleeding from the nose or oropharynx; endotracheal intubation can be difficult; and only a smaller than usual endotracheal tube may fit through the larynx. Airway resistance is reduced, probably due to the progesterone-mediated relaxation of the bronchial musculature. The high level of progesterone, a hormone produced continuously during pregnancy, signals the brain to lower the level of carbon dioxide in the blood. As a result, a pregnant woman breathes slightly faster and more deeply to exhale more carbon dioxide and keep the carbon dioxide level low. She may breathe deeper and faster also because the enlarging uterus limits how much the lungs can expand when she breathes in. The circumference of the woman's chest enlarges slightly. Virtually every pregnant woman becomes somewhat more out of breath when she exerts herself, especially toward the end of pregnancy. During exercise, the breathing rate increases more when a woman is pregnant than when she is not.

Lung Volumes Alterations occurring in lung volumes and capacities during pregnancy include the following: Dead volumes increases owing to relaxation of the musculature of conducting airways. Tidal volumes increases gradually (3550%) as pregnancy progresses. Total lung capacity is reduced (4-5%) by the elevation of the diaphragm. Functional residual capacity, residual volume, and respiratory reserve volume all decrease by about 20%.Larger tidal volume and smaller residual volume cause increased alveolar ventilation (about 65%) during pregnancy. Inspiratory capacity increases 5-10%. Functional respiratory changes include a slight increase in respiratory rate, a 50% increase in minute ventilation, a 40% increase in tidal volume, and a progressive increase in oxygen consumption of up to 15-20% above non-

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pregnant levels by term. With the increase in respiratory tidal volume associated with a normal respiratory rate, there is an increase in respiratory minute volume of approximately 26%. As the respiratory minute volume increases, hyperventilation of pregnancy occurs, causing a decrease in alveolar CO2 . This decrease lowers the maternal blood CO2 tension; however alveolar oxygen tension is maintained within normal limits. Maternal hyperventilation is considered a protective measure that prevents the fetus from the exposure to excessive levels of CO2. Ventilation and Respiratory Gases A progressive increase in minute ventilation starts soon after conception and peaks at 50% above normal levels around the second trimester. This increase is effected by a 40% rise in tidal volume and a 15% rise in respiratory rate (2-3 breaths/minute). Since dead space remains unchanged, alveolar ventilation is about 70% higher at the end of gestation. Arterial and alveolar carbon dioxide tensions are decreased by the increased ventilation. An average PaCO2 of 32 mmHg (4.3 kPa) and arterial oxygen tension of 105 mmHg (13.7 kPa) persist during most of gestation. The development of alkalosis is forestalled by compensatory decreases in serum bicarbonate. Only carbon dioxide tensions below 28 mmHg (3.73 kPa) will lead to a respiratory alkalosis. During labor, ventilation may be further accentuated, either voluntarily (Lamaze method of pain control and relaxation) or involuntarily in response to pain and anxiety. Such excessive hyperventilation results in marked hypocarbia and severe alkalosis, which can lead to cerebral and uteroplacental vasoconstriction and a left shift of the oxygen dissociation curve. The latter reduces the release of oxygen from hemoglobin with consequent decreased maternal tissue oxygenation as well as reduced oxygen transfer to the fetus. Furthermore, episodes of hyperventilation may be followed by periods of hypoventilation as the blood carbon dioxide tension (PaCO2) returns to normal. This may lead to both maternal and fetal hypoxia. Oxygen consumption increases gradually in response to the needs of the growing fetus, culminating in a rise of at least 20% at term. During labor, oxygen consumption is further increased (up to and over 60%) as a result of the exaggerated cardiac and respiratory work load. Effects of Labor on the Pulmonary System There is a further decrease in functional residual capacity (FRC) during the early phase of each uterine contraction, resulting from redistribution of blood from the uterus to the central venous pool. Because this decrease in FRC occurs without a concomitant change in dead space, there is little residual dilution and, therefore, presumably more efficient gas exchange. Clinical Implications

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The changes in respiratory function have clinical relevance for the anesthesiologist. Most importantly, increased oxygen consumption and the decreased reserve due to the reduced functional residual capacity, may result in rapid falls in arterial oxygen tension despite careful maternal positioning and preoxygenation. Even with short periods of apnea, whether from obstruction of the airway or inhalation of a hypoxic mixture of gas, the gravida has little defense against the development of hypoxia. The increased minute ventilation combined with decreased functional residual capacity hastens inhalation induction or changes in depth of anesthesia when breathing spontaneously. Gastrointestinal System Since aspiration of gastric contents is an important cause of maternal morbidity and mortality in association with anesthesia, an examination of the controversy surrounding gastrointestinal changes in pregnancy is justified. Mechanical Changes The enlarging uterus causes a gradual cephalic displacement of stomach and intestines. At term the stomach has attained a vertical position rather than its normal horizontal one. These mechanical forces lead to increased intragastric pressures as well as a change in the angle of the gastroesophageal junction, which in turn tends toward greater esophageal reflux. Physiological Changes The hormonal effects on the gastrointestinal tract are an issue of debate among anesthetists. Relaxation of the lower esophageal sphincter has been described, but there have been differing views about the effect on motility of the gastrointestinal tract and the times at which it is most prominent. Many believe that there is also retardation of gastrointestinal motility and gastric emptying, producing increased gastric volume with decreased pH, beginning as early as 8-10 weeks of gestation. Recent studies, however, have shed a different light on the subject. Measuring peak plasma concentrations of drugs absorbed exclusively in the duodenum in both non-pregnant and pregnant volunteers, at different times of gestation, it was shown that peak absorption occurred at the same interval in all women with the exception those in labor. This suggests that gastric emptying is delayed only at the time of delivery. Thus, the raised risk of aspiration is due to an increase of esophageal reflux and decreased pH of gastric contents. The heightened incidence of difficult endotracheal intubations worsens the situation. Oral Cavity
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Salivation may seem to increase due to swallowing difficulty associated with nausea, and, if the pH of the oral cavity decreases, tooth decay may occur. Tooth decay during pregnancy, however, is not due to lack of calcium in the teeth. Indeed, dental calcium is stable and not mobilized during pregnancy as is bone calcium. The gums may become hypertrophic, hyperemic and friable; this maybe due to increased systemic estrogen. Vitamin C deficiency also can cause tenderness and bleeding of the gums. The gums should return to normal in the early puerperium. Gastrointestinal Motility Gastrointestinal motility may be reduced during pregnancy due to increased levels of progesterone, which in turn decrease the production of motilin, a hormonal peptide that is known to stimulate smooth muscle in the gut. Transit time of food throughout the gastrointestinal tract may be so much slower that more water than normal is reabsorbed, leading to constipation. Stomach and Esophagus Gastric production of hydrochloric acid is variable and sometimes exaggerated, especially during the first trimester. More commonly, gastric acidity is reduced. Production of the hormone gastrin increases significantly, resulting in increased stomach volume and decreased stomach pH. Gastric production of mucus may be increased. Esophageal peristalsis is deceased, accompanied by gastric reflux because of the slower emptying time and dilatation or relaxation of the cardiac sphincter. Gastric is more prevalent in later pregnancy owing to elevation of the stomach by the enlarged uterus. Besides leading to heartburn, all of these alterations as well as lying in the supine lithotomy position make the use of anesthesia more hazardous because of the increased possibility of regurgitation and aspiration. Small and Large Bowel and Appendix The large and small bowel moves upward and laterally, the appendix is displaced superiorly in the right flank area. These organs return to the normal positions in the early puerperium. As noted previously, motility is generally decreased and gastrointestinal tone is decreased. Gallbladder Gallbladder function is also altered during pregnancy because of the hypotonia of the smooth muscle wall. Emptying time is slowed and often incomplete. Bile can become thick, and bile stasis may lead to gallstone formation.

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Liver There are no apparent morphologic changes in the liver during normal pregnancy, but there are functional alterations. Serum alkaline phosphatase activity can double, probably because of increased placental alkaline phosphatase isoenzimes. Thus, a decrease in the albumin/globulin ratio occurs normally in pregnancy. Pulmonary Aspiration of gastric contents can occur either following vomiting (active) or regurgitation (passive). Aspiration of solid material causes atelectasis, obstructive pneumonitis or lung abscess, while aspiration of acidic gastric contents results in chemical pneumonitis (Mendelson's syndrome). The most serious consequences follow aspiration of acidic materials containing particulate matter as may follow swallowing certain antacids such as magnesium trisilicate. Clear antacids such as sodium citrate (0.3 Mol) or bicarbonate should be used. While the incidence of pulmonary aspiration of solid food has decreased due to patient education, that of gastric acid has remained constant.

Clinical Implications The danger of aspiration is almost eliminated when regional anesthesia or inhalational analgesia is used. During general anesthesia airway protection by means of a cuffed endotracheal tube is mandatory. Although awake intubation is safest, discomfort and the lack of patient cooperation and discomfort prevent it being the routine method for securing the airway. The endotracheal tube is placed immediately following loss of consciousness after induction of general anesthesia. The acidity and volume of gastric content can be reduced by pharmacologic interventions which may prove invaluable. Most importantly, a nonparticulate oral antacid, 30ml of sodium citrate 0.3 Mol or bicarbonate, should be given immediately prior to induction of general anesthesia to all women. In addition, if available, metoclopramide, 10 mg IV, should be administered 15-30 minutes before induction to promote gastric emptying and increase the lower esophageal sphincter tone. This is especially beneficial in women in labor who have not been starved and and require emergency surgery. Lastly, histamine H2-receptor antagonist the night before and the morning of delivery may reduce secretion of hydrochloric acid (ranitidine 150mg orally).
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Metabolism

All metabolic functions are increased during pregnancy to provide for the demands of fetus, placenta and uterus as well as for the gravida's increased basal metabolic rate and oxygen consumption. Protein metabolism is enhanced to supply substrate for maternal and fetal growth. Fat metabolism increases as evidenced by elevation in all lipid fractions in the blood. Carbohydrate metabolism, however, demonstrates the most dramatic changes. Metabolically speaking, pregnant women live in a state of "accelerated starvation." First, nutritional demands of the growing fetus are met by the intake of glucose and, second, secretion of insulin in response to glucose is augmented. As early as 15 weeks of gestation, maternal blood glucose levels after an overnight fast are considerably lower than in the nongravid state. As the fetus and placenta grow and place increasing demands on the mother, phenomenal alterations in metabolism occur. The most obvious physical changes are weight gain and altered body shape. Weight gain is due not only to the uterus and its contents but also to increase breast tissue, blood and water volume in the form of extravascular and extracellular fluid. Deposition of fat and protein and increased cellular water are added to the maternal stores. The average weight gain during pregnancy is 12,5Kg. During normal pregnancy, approximately 1000g of weight gain is attributable to protein. Half of this is found in the fetus and the placenta, with the rest being distributed as uterine contractile protein, breast glandular tissue, plasma protein, and hemoglobin. Plasma albumin levels are decreased and fibrinogen levels increased. Total body fat increases during pregnancy, but the amount varies with total weight gain. During the second half of pregnancy, plasma lipids increase, but triglycerides, cholesterol and lipoproteins decrease soon after delivery. The ratio of low density lipoproteins to high density lipoproteins increases during pregnancy. Hypoglycemia Optimal blood glucose levels in pregnant women range between 4.4 to 5.5 mmol/1 (80 to 100mg/dl). In healthy non-pregnant individuals, signs of hypoglycemia usually begin when the blood glucose level declines to approximately 2.2 mmol/1 (40mg/dl); in pregnant women, however, hypoglycemia is defined as a concentration below 3.3 mmol/1 (60mg/dl). Hypoglycemia initiates the release of glucagon, cortisol and, importantly, catecholamines. In the anaesthetized state, however, these compensatory mechanisms, particularly the release of epinephrine (adrenaline), are blocked. Autonomic derangements in the form of hypotension and tachycardia tend to ensue during high regional blockade or deep general anesthesia, which may mask the symptoms and signs of hypoglycemia. Renal Physiology
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Renal Dilatation During pregnancy, each kidney increases in length by 1-1,5cm, with a concomitant increase in weight. The renal pelvis is dilated. The ureters are dilated above the brim of the bony pelvis. The ureters also elongate, widen, and become more curved. Thus there is an increase in urinary stasis, this may lead to infection and may make tests of renal function difficult to interpret. The absolute cause of hydonephrosis and hydroureter in pregnancy is unknown, there may be several contributing factors: 1. Elevated progesterone levels may contribute to hypotonia of the smooth muscle in the ureter. 2. The ovarian vein complex in the suspensory ligament of the ovary may enlarge enough to compress the ureter at the brim of the bony pelvis, thus causing dilatation above that level. 3. Dextrorotation of the uterus during pregnancy may explain why the right ureter is usually more dilated than the left. 4. Hyperplasia of smooth muscle in distal one-third of the ureter may cause reduction in the luminal size. Renal Function The glomerular filtration rate (GFR) increases during pregnancy by about 50% .The renal plasma flow rate increases by as much as 25-50%. Urinary flow and sodium excretion rates in late pregnancy can be altered by posture, being twice as great in the lateral recumbent position as in the supine position. Even though the GFR increased dramatically during pregnancy, the volume of the urine passed each day is not increased. Thus, the urinary system appears to be even more efficient during pregnancy. With the increase in GFR, there is an increase in endogenous clearance of creatinine. The concentration of creatinine in serum is reduced in proportion to increase in GFR, and concentration of blood urea nitrogen is similarly reduced. Glucosuria during pregnancy is not necessarily abnormal, may be explained by the increase in GFR with impairment of tubular reabsorption capacity for filtered glucose. Increased levels of urinary glucose also contribute to increased susceptibility of pregnant women to urinary tract infection. Proteinuria changes little during pregnancy and if more than 500mg/24h is lost, a disease process should be suspected Levels of the enzyme renin, which is produced in kidney, increase early in the first trimester, and continue to arise until term. This enzyme acts on its substrate angiotensinogen, to first form angiotensin1 and then angiotensin2, which acts as a vasoconstrictor. Normal pregnant are resistant to the pressor effect of elevated levels of angiotensin2 but those suffering from preeclampsia are not resistant, this is one of the some theories to explain this disease.

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Bladder As the uterus enlarges; the urinary bladder is displaced upward and flattened in the anterior-posterior or diameter. Pressure from the uterus leads to increase in urinary frequency. Bladder vascularity increases and muscle tone decreases, increasing capacity up to 1500ml. Drug Responses The response to anesthetic and adjuvant drugs is modified during pregnancy and the early puerperium. The most pertinent alteration is a reduced drug requirement, manifest in both regional and general anesthesia. Regional Anesthesia From the late first trimester to the early puerperium, a smaller dose of local anesthetic is required to obtain the desired level of spinal or extradural blockade. During the last months of gestation, approximately two-thirds of the normal dose is adequate. This altered response, which is due to CSF and hormonal changes and an increase in volume of the epidural veins, subsides progressively in the early postpartum period. General Anesthesia Induction and changes in depth of inhalation anesthesia occur with greater rapidity in pregnant women than in non-pregnant subjects. Pregnancy enhances anesthetic uptake in two ways. The increase in resting ventilation delivers more agent into the alveoli per unit time, while the reduction in functional residual capacity favors rapid replacement of lung gas with the inspired agent. In addition, there is a reduction in anesthetic requirements, with a fall in the minimum alveolar concentrations (MAC) of halogenated vapors. When measured in ewes MAC was 25-40% lower in gravid as compared with nonpregnant animals. The decreased functional residual capacity has a further effect on the management of general anesthesia. As referred to earlier, the resultant reduction in oxygen storage capacity, together with the elevated oxygen consumption, leads to an unusually rapid decline in arterial oxygen tension in the apnoeic anaesthetized gravida. There are also alterations in the response to intravenous agents, in particular prolongation of their elimination half-lives consequent to the greater distribution volume (resulting from the pregnancy-induced increase in plasma volume). Thus, the mean elimination half-life for thiopentone in gravid women is more than doubled in comparison with that in nongravid young patients.

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Serum Cholinesterase Serum cholinesterase levels fall by 24-28% during the first trimester without a marked change for the remainder of gestation. However, even lower levels (about 33% reduction) develop during the first 7 postpartum days. The decreased levels of the enzyme are still sufficient for normal hydrolysis of clinical doses of suxamethonium or chloroprocaine during gestation. Postpartum, however, approximately 10% of women will be at risk of a prolonged reaction to suxamethonium.

Clinical Implication These altered drug responses must be taken into consideration whenever a patient is pregnant or in the early puerperium.

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References Internet Articles

1. 2. 3. 4.

http://www.patient.co.uk/doctor/Physiological-Changes-In-Pregnancy.htm http://www.medstudents.com.br/ginob/ginob5.htm http://www.nda.ox.ac.uk/wfsa/html/u09/u09_005.htm http://www.merckmanuals.com/home/sec22/ch257/ch257d.html

Document Readings Thornburg KL, Jacobson SL, Giraud GD, et al; Hemodynamic changes in pregnancy.; Semin Perinatol. 2000 Feb;24(1):11-4. [abstract] 2. Chesnutt AN; Physiology of normal pregnancy.; Crit Care Clin. 2004 Oct;20(4):609-15. [abstract] 3. Oxford Textbook of Nephrology by Davison, Grunfeld, Cameron and Stewart. OUP 2nd edition ISBN 019262413X
1.

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II. Pharmacodynamics In Pregnant Patient

Ma Lourdes Arquiza PHARMACODYNAMICS The science dealing with interactions between the chemical components of living systems and the foreign chemicals, including drugs that enter those systems.

PHARMACOKINETICS Involves the study of absorption, distribution, metabolism and excretion of drugs.

MATERNAL DRUG ACTION Because any medication can present risks in pregnancy, and because not all risks are known, the safest pregnancy-related pharmacy is as little pharmacy as possible. A single intrauterine exposure to a drug can affect structures undergoing rapid development at the time exposure. Thalidomide is an example of a drug that profoundly affects the development of the limbs after the only brief exposure. This exposure, however must be at a critical time in the development of limbs. The greatest risk is during the 1st 3 months of gestation. Drugs have a direct effect on maternal tissues with secondary or indirect effects on fetal tissues. Drugs may interfere with the passage of oxygen or nutrition through the placenta and have direct effects on the fetus.

PREGNANCY CATEGORY The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does not include any risks conferred by pharmaceutical agents or their metabolites that are present in breast milk. Every drug has specific information listed in its product literature. In the UK, while no preset categories are applied, the British National Formulary gives a table of drugs to be avoided or used with caution in pregnancy, and does so using a limited number of key phrases. In 1979, the United States Food and Drug Administration (FDA) introduced a classification of fetal risks due to pharmaceuticals. This was based on a similar system that was introduced in Sweden one year earlier.

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Different Pregnancy categories in the United States FDA Pharmaceuticals Pregnancy Categories
Pregnancy Category A Adequate and well-controlled human studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters). Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

Pregnancy Category B

Pregnancy Category C

Pregnancy Category D

Pregnancy Category X

Australia has a slightly different pregnancy category system from the United States - notably the subdivision of Category B. The system, as outlined below, was established by the Congenital Abnormalities Sub-committee of the Australian Drug Evaluation Committee (ADEC).
Pregnancy Category A ADEC Pregnancy Categories Drugs which have been taken by a large number of
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Pregnancy Category B

Pregnancy Category B2

Pregnancy Category B3

Pregnancy Category C

Pregnancy Category D

Pregnancy Category X

pregnant women and women of childbearing age without an increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed. Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage. Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage. Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. Drugs which, owing to their pharmaceutical effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Drugs that have such a high risk of causing permanent damage to the fetus that they should NOT be used in pregnancy or when there is a possibility of pregnancy.

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CATEGORY OF SELECTED AGENTS

The data presented is for comparative and illustrative purposes only, and may have been superseded by updated data

Classification of some agents, based on different national bodies Pharmaceutical agent Australia United States Acetaminophen/Parac A B etamol Amoxicillin A B Amoxicillin with B1 B clayulanic acid Cefotaxime B1 B Diclofenac C C Isotretinoin X X Leflunomide X X Loperamide B3 B Paroxetine C D Phenytoin D D Rifampicin C C Thalidomide X X Theophylline A C Tetracycline D D Triamcinolone (skin) A C

THERAPEUTIC DRUG ACTIONS IN THE FETUS A substance that has healing or preventive properties in relation to certain diseases, or is administered to enable a medical diagnosis. Any product that is claimed to cure or prevent a disease is a therapeutic drug. Before it can be sold in France, it must obtain a French or European marketing authorization, following tests that prove its quality, harmlessness and efficacy. A therapeutic drug can only be sold in a pharmacy, and those that are classed as dangerous are only supplied on prescription. TOXIC DRUG ACTION TO THE FETUS The absence of drug- induced toxicity in the mother does not assure us of the drugs relative safety for her developing fetus.
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Drugs taken during the first trimester of pregnancy, as little as the single dose has been demonstrated to produce severe physical deformities (teratogenic effects) in the human fetus. Teratogenesis is a prenatal toxicity characterized by structural or functional defects in the developing embryo or fetus. TRIMESTER First All All EFFECT Multiple gross anomalies Eighth nerve toxicity Cystic cerebral cortical lesions, abnormal developmental patterns, decreased school performance MASCULINIZATION OF FEMALE FETUS Increased risk of gray baby syndrome Increased risk of spontaneous abortion, abruptio placenta, and premature labor Cleft palate Chronic use leads to neonatal dependence Malformations of lower ext. High risk of fetal alcohol syndrome Chronic use leads to neonatal dependence Congenital goiter, hypothyroidism Cardiovascular defects May be mutagenic ( from animal studies; there is no evidence for teratogenic effects in humans Cutis laxa, other congenital malformations Abnormal neurologic examination, poor suck

DRUG AMINOPTERIN AMINOGLYCOSIDES AMPHETAMINES

ANDROGENS CHLORAMPHENICOL COCAINE

2nd and 3rd 3rd All

CORTISONE DIAZEPAM DISULFIRAM ETHANOL HEROIN IODIDE LITHIUM METRONIDAZOLE

1st All 1st All All All 1st 1st

PENICILLAMINE PHENCYCLIDINE

1st All

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PHENYTOIN PROGESTIN TETRACYCLINE VACCINES AND LIVE VIRUS VALPROIC ACID WARFARIN

All All All All All First Third

reflex and feeding Cleft lip and palate Ambiguous genitalia, cardiovascular defects Discoloration and defects of teeth and altered bone growth Risk of fetal infection with attenuated viruses Various congenital anomalies Especially spina bifida Hypoplastic nasal bridge Risk of bleeding

TERATOGENIC DRUG ACTIONS Teratogens any substance that interferes with the normal fetal development causing one or more developmental abnormalities

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Selected Established and Suspected Human Drug Teratogens Drug /Class Therapuetic uses Primary types of teratogenesis Adrenocorticosteroids Inflammatory disorders Cleft palate (DEXAMETHASONE) ALCOHOL Alcoholic beverages Fetal alcohol syndrome ANDROGENS Gynecological disorders Masculinization of and cancer in woman external genitalia of the female offspring ANTICANCER AGENTS Cancer chemotherapy Very high incidence of teratogenesis ANTICOAGULANTS Retard blood clotting Eye and nose defects (WARFARIN) ANTICONVULSANTS Epilepsy Mental retardation, heart (PHENYTOIN) defects, celft palate ESTROGENS Threatened abortion Females: no menstrual cycle at puberty Male: defects in genital organs OXYGEN Premature infants Blindness (@ o2 concentrations > 40%) VITAMIN D Prevention or tx of Bone deformities vitamin deficiencies

III.

NURSES ROLE IN DRUG ADMINISTRATION TO PREGNANT WOMEN

Kishia Olarte

When a woman becomes pregnant, it is very important for her to lead a healthy life: to eat plenty of nourishing food, get plenty of rest, and exercise regularly. It is also vital that she avoid anything that might harm her or her baby-to-be. It is especially important to give up alcohol, cigarettes, and drugs. For a pregnant woman, drug abuse is doubly dangerous. First, drugs may harm her own health, interfering with her ability to support the pregnancy. Second, some drugs can directly impair prenatal development. Virtually all illegal drugs, such as heroin and cocaine, pose dangers to a pregnant woman. Legal substances, such as alcohol and tobacco, are also dangerous, and even medical drugs, both prescription and over-the-counter, can be harmful. For her own health and the health of her baby-to-be, a woman should avoid all of them as much as possible, from the time she first plans to become pregnant or learns that she is pregnant. Many medications have side effects that are potentially harmful during pregnancy, but their benefits may outweigh their risks. A woman should consult her doctor or midwife before taking any drug, even one sold over the counter. Below are a few examples of medical drugs that must be used with extreme caution or avoided altogether. Isotretinoin (Accutane) and etretinate (Tegison) are used to treat chronic acne and psoriasis. They may cause chronic malformations during the stage of organ development. Anticonvulsants, such as phenytoin (Dilantin) and carbamezapine (Tegretol), are used to prevent epileptic seizures. They are associated with defects of the heart and face, as well as mental retardation. Antimigraine drugs, such as ergotamine and methysergide, are used to head off migraine attacks but raise the risk of premature labor. Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs (NSAIDs) interfere with blood clotting and increase the risk of uncontrolled bleeding for both mother and baby. Toward the end of pregnancy, they hinder production of the hormones that stimulate labor, so that labor may be dangerously delayed or extended. Anticoagulant drugs based on coumarin are used in the treatment of heart disease and stroke, to slow blood clotting. Taken during early pregnancy, they are associated with facial malformations and mental retardation. Later on they raise the risk of uncontrolled bleeding. Antepartum Drugs
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Assessment: Gather comprehensive medical, drug (illicit, non-pharmacologic and pharmacologic), and herbal history.

Obtain baseline vital signs. Identify client risk for substance abuse and collaborate with other professionals to plan strategies to minimize risks. Assess drug history to determine whether antacid use will interfere with absorption. Review history of aspirin use when admitting a client in labor. If aspirin has been used, alert the staff and monitor for increased bleeding. Ascertain any medical history of alcoholism, liver disease, viral infection, and renal deficiencies. Acetaminophen should be used cautiously in these clients.

Nursing Interventions: General Be cognizant that drug use may be part of multiple substance abuse and may also involve maternal-neonatal infections. Stress the importance of prenatal care, and discuss fears client may have about health care professionals and concerns about legal action in the event of substance abuse. Specific Instruct on nonpharmacologic and pharmacologic measures to relieve common pregnancy discomforts. Refer to tobacco, alcohol, or drug treatment program if appropriate. Instruct on nutritional and therapeutic supplements needed during pregnancy. Monitor hemoglobin/hematocrit of prenatal clients per agency protocol. Iron Question client about nausea, constipation and bowel habit changes if taking iron preparations. Give diluted liquid iron preparation through a plastic straw to prevent discoloration of teeth. Store iron in a light-resistant container. Be cognizant that client may have false-positive result of occult blood in stool if taking iron.

Client Teaching: General Advise pregnant woman that tobacco, alcohol, and heavy caffeine use may have adverse effects on the fetus. Instruct client that before taking drugs (illicit, OTC, prescribed) to discuss with health care provider secondary to teratogenic potential.

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Aspirin/Acetaminophen

Advise client not to take aspirin, during pregnancy particularly during the third trimester. Instruct client not to take nonsteroidal anti-inflammatory drugs (NSAIDs) with acetaminophen. Caffeine/Alcohol/Nicotine

Advise client to limit coffee and caffeine ingestion from none to 1 to 2 cups per day and to limit other sources of caffeine (tea, cola, soft drinks, chocolate, and certain drugs). If caffeine is allowed by the health care provider, teach client to space limited caffeine intake evenly throughout the day because caffeine passes readily to the fetus that cannot metabolize it. Caffeine can decrease intervillious placental blood flow. Advise client to use decaffeinated products or dilute caffeinated products. Instruct client not to drink alcohol if she is pregnant because no safe level of alcohol has been determined and even minimal exposure have resulted in fetal alcohol effect and moderate/excess exposure has resulted in fetal alcohol syndrome. Advise client that smoking can cause the loss of nutrients such as vitamins A and C, folic acid, cobalamin and calcium. Tobacco use may contribute to a shortened gestation and low birth weight infants. Antacids

Iron

Advise that antacids should not be taken within one hour of taking an enteric-coated tablet because the acid-resistant coating may dissolve in the increased alkaline condition of the stomach, and the medication will not be released in the intestine as needed. Stomach upset may result. Advise client to store antacid liquid suspension at room temperature, not to let it freeze, and to shake the bottle well before pouring. Instruct client about dietary sources of iron, which include organ meats (liver), red meat, nuts and seeds, wheat germ, spinach, broccoli, prunes, and iron fortified cereals. Explain to client that if supplemental iron is taken between meals, increased absorption (and also increased side effects) may result. Taking iron one hour before meals is suggested. Give with juice or water but not with milk or antacids.
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Self-Administration for Iron and Antacids

Advise client to swallow the iron tablets whole, not to crush them. Liquid iron preparations should be taken with a plastic straw to avoid staining the teeth. Caution client not to take antacids with iron because antacids impair absorption and are generally discouraged during pregnancy. Iron and antacids should be taken two hours apart if both are prescribed.

Side Effects for Iron and Antacids Advise client that there may be a change in bowel habits when taking antacids. Aluminum products can cause constipation, whereas magnesium products can cause diarrhea. Many antacids contain both ingredients. Advise client to keep iron tablets away from children. Iron tablets look like candy, and death has been reported in small children who have ingested 2 g or less of ferrous sulfate. Beta2-adrenergic agonists: Brethine (Terbutaline) Beta-sympathomimetic drugs act by stimulating beta2-receptors on smooth muscle. The frequency and intensity of uterine contractions decrease as the muscle relaxes. Terbutaline (Brethine) is commonly used. It is approved for medicinal use but not specifically as a tocolytic. Terbutaline can effectively decrease uterine contractions; however, the literature indicates that knowledge about the long-term effects of this drug is still lacking.

Assessment: Identify risks for preterm labor (PTL) early in pregnancy. When a client has preterm uterine contractions, obtain a history, complete physical assessment, vital signs, fetal heart rate (FHR), and urine specimen for screening for intrauterine infection and urinary tract infection.

Nursing Interventions: Monitor and assess uterine activity and FHR. Maintain client in left lateral position as much as possible to facilitate uteroplacental perfusion. Monitor vital signs per unit protocol, specifically maternal pulse. Report maternal heart rate greater than 110beats/min. Report auscultated cardiac dysrhythmias. An electrocardiogram (ECG) may be ordered.

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Auscultate breath sounds every 4 hours. Notify health care provider if respirations are more than 30 per minute or if there is a change in quality (wheezes, rales, coughing). Monitor daily weight to assess fluid overload: strict input and output (I and O) measurement. Report baseline FHR that is more than 180 beats/min or any significant increase in uterine contractions from pretreatment baseline. Report persistence of uterine contractions despite tocolytic therapy. Report leaking of amniotic fluid, any vaginal bleeding or discharge, or complaints of rectal pressure. Be alert to presence of hypoglycemia and hyperglycemia in the newborn within 5 hours of discontinued beta-sympathomimetic drugs. Assist clients on bed rest and home tocolytic therapy to plan for assistance with self-care and family responsibilities.

Client Teaching: General Inform client of the signs and symptoms of PTL (menstrual-type cramps, sensation of pelvic pressure, low backache, increased vaginal discharge, and any abdominal discomfort). Instruct client that if she experiences PTL contractions, initially she should void, recline on her left side to increase uterine blood flow, and drink extra fluids. Emphasize that she should notify her health care provider if the uterine contractions do not cease or if they increase in frequency. Explain side effects of beta-sympathomimetic drugs. Report heart palpitations or dizziness to health care provider. Instruct client to take drugs regularly and as prescribed. Advise client to contact the health care provider before taking any drugs while on tocolytic drug therapy. CORTICOSTEROID THERAPY IN PRETERM LABOR The desired outcome from tocolytic therapy is prevention or cessation of PTL. Clients (24 to 34 weeks gestation) at risk for preterm delivery should receive antenatal corticosteroid therapy with betamethasonbe (Celestone) or dexamethasone. Administration of corticosteroids accelerates lung maturation with resultant surfactant development in the fetus in utero, thereby decreasing the incidence and severity of respiratory distress syndrome (RDS) with increased survival of preterm infants. Antenatal therapy decreases infant mortality, RDS and intraventicular bleeds in neonates born between 24 to 34 gestational weeks. The effects and benefits of corticosteroid administration are believed to begin 24 hours after administration and last for up to 1 week.

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Betamethasone (Celestone) When PTL occurs before the 33rd week of gestation, corticosteroid therapy with betamethasone may be prescribed, 12 mg intramuscularly (IM) every 24 hours for two doses. Adverse Reactions Side effects of betamethasone are rare but include seizures, headache, vertigo, edema, hypertension, increased sweating, petechiae, eccymoses, and facial erythema. Assessment: Assess for history of hypersensitivity. Assess vital signs; report abnormal findings. Assess fetal heart rate (FHR)

Nursing Interventions: Shake the suspension well. Avoid exposing to excessive heat or light. Inject into large muscle, but not the deltoid, to avoid local atrophy. Monitor maternal vital signs. Maintain accurate intake and output. Check blood glucose if used for client with diabetes. DRUG FOR PREGNANCY-INDUCED HYPERTENSION Pregnancy-induced hypertension (PIH), the most common serious complication of pregnancy, can have devastating maternal and fetal effects. However, with proper management, the prognosis for both mother and infant is good. Hypertensive disorders are reported in 6% to 30% of all pregnant clients, with 3% to 8% of all pregnancies reflecting incidence of PIH. The condition is most often observed after 20 weeks gestation intrapartum and during the first 72 hours postpartum. The cause of PIH remains unknown, although numerous hypotheses exist. Assessment: Review baseline vital signs from early pregnancy and BP readings during prenatal visits. Identify client history that may predispose client to pregnancy-induced hypertension (PIH).
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Nursing Interventions: Magnesium Sulfate Continuous electronic fetal monitoring. Monitor for maternal toxicity. Lethargy and weakness result from the blocking of the neuromuscular transmission .Diaphoresis, flush feeling of warmth, and nasal congestion are the results of the vasodilation from relaxation of smooth muscle. Have airway suction, resuscitation equipment and emergency drugs available. Have antidote available Calcium gluconate (1g) IV is given over 3 minutes. Maintain client in left lateral recumbent position in low-stimulation environment. provide close observation For IM administrator, use Z-track technique and rotate sites (drug is painful and irritating) . Infrequent administration Monitor BP, pulse, and respiratory rate per agency protocol, DTR, clonus and hourly I & O with urimeter for output Monitor temperature breath sound and bowel sound every 4 hours Check urine for protein every hour Asses for epigastric pain (heralds impending seizure), headache, visual symptoms (blurred vision and scotoma), sensory changes, edema, level of consciousness, and seizure activity on ongoing basis. Monitor serum magnesium levels according to agency protocol for range between 4 and 7 mg/dl. Notify physician if following are observed: Respiratory less than 12/min Absence of DTR Urinary output less than 30 ml/h Systolic BP greater than or equal to 160 mm Hg, unless ordered otherwise Magnesium level greater than 7 mEq/L Absent bowel sounds or altered breath sound Epigastric pain, headache, visual symptoms (blurred vision and scotoma), sensory changes, change in affect or level of consciousness, seizure activity Monitor laboratory reports: evidence of low platelet count, and, if present, observe for excessive bleeding. Monitor fetal status. FHR baseline should remain to 110 to 160. Monitor laboratory results: 24 hours urinary protein result if ordered (>300 mg/24 h is abnormal). Monitor client for magnesium toxicity. Monitor newborn for effects of placental exposure to excess magnesium sulfate. Although infrequent, newborn side effects include lethargy, neurologic or respiratory depression, and muscle hypotonia.

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Hydralazine Take pulse and BP every 5 minutes when drug is administered or monitor with electronic BP device until stabilized and then every 15 minutes, Maintain diastolic BP between 90 and 110 mm HG or as ordered. Observe for change in level of consciousness and headache. Monitor I and O to avoid hypotensive episodes or overload. Monitor fetal heart rate (FHR).

Client Teaching: General Instruct client to avoid exposure to infection. Remind client with diabetes to check her glucose level as ordered. Side Effects Instruct client to report immediately any breathing difficulty, weakness, or dizziness. Instruct client to report changes in stool, easy bruising, bleeding blurred vision, unusual weight gain and emotional changes.

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PHARMACOKINETICS IN PREGNANT PATIENTS Aaron Alvarez

Pharmacokinetics describes the handling of a drug by the body how the drug is absorbed, distributed and eliminated and how these processes determine plasma concentrations of the drug. Changes in maternal physiology during pregnancy influence pharmacokinetics, and this may have important sequelae for drug dosing, especially for drugs for which adverse effects occur at concentrations within, or just above, the therapeutic range. For many drugs absorption is decreased and elimination increased, thus tending to reduce plasma concentrations. There are, however, relatively few specific data on pharmacokinetics in pregnancy, compared to the non-gravid state, because of the obvious ethical issues surrounding studies during pregnancy. Most therapeutic guidelines are thus based on observational studies and basic principles. The therapeutic actions of most drugs, and often their adverse effects, are determined by the concentration of the drug in plasma. An understanding of pharmacokinetics is thus essential in determining practical aspects of drug delivery dose, dose frequency and route of administration in order to achieve plasma concentrations that are sufficient to produce desired therapeutic effects while minimizing the risk of dose-related adverse or toxic effects. In the case of physiological changes in drug handling, such as those occurring during pregnancy, a detailed knowledge of the pharmacokinetics of a drug potentially provides the necessary information to modify dose schedules to ensure efficacy and minimize the risk of toxicity. ORAL ABSORPTION AND BIOAVAILBILITY When drugs are delivered via the oral route, as is usually the case, absorption occurs mainly by passive diffusion of the drug through the small intestine. The bioavailability of a drug is a measure of the proportion of the drug that reaches the systemic circulation in comparison with the amount that would reach the systemic circulation were the drug to be given intravenously. It is usually less than 100% as a result of incomplete absorption. In some cases delivery to the systemic circulation may be greatly attenuated as a result of first-pass metabolism-the drug being metabolized within the liver before reaching the systemic circulation. Opioids are examples of drugs that have low bioavailability due to a high firstpass metabolism, and they are often given by intramuscular injection to avoid this problem. It is important to note that bioavailability only gives information regarding the total extent of absorption, not the rate of absorption, so that the peak plasma concentration (Cmax) and time of peak plasma concentration (Tmax) following an oral dose may differ even though bioavailability may remain constant.

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DISTRIBUTION AND VOLUME OF DISTRIBUTION Drugs reaching the systemic circulation are distributed to varying degrees within the intravascular, interstitial and intracellular spaces. The relative distribution of a drug within these compartments depends upon its relative solubility in water and within cell membranes, polar drugs being contained mainly within the extracellular space and lipophilic drugs being more widely distributed. The degree to which drugs are bound to plasma proteins also influences their distribution. It is the volume that the drug would be distributed in if it were uniformly and instantaneously distributed at a concentration equal to that in the plasma. Drugs that are confined to the intravascular compartment (e.g. by virtue of their large molecular weight as in the case of heparin) have the lowest Vd, with Vd then approximating total plasma volume. Widely distributed lipophilic drugs have a large Vd. DRUG CLEARANCE Polar drugs tend to be eliminated by the kidneys whereas lipophilic drugs are usually metabolized by the liver to more polar metabolites which are then eliminated by the kidneys. Metabolism is a two-stage process, phase I usually involving modification (e.g. oxidation, reduction and hydrolysis) and phase II conjugation (e.g. acetylation and methylation). Other routes of elimination, such as excretion in bile or via the airways, tend to be of minor importance. The clearance of a drug is the amount of plasma cleared of drug per unit time. Drugs are cleared mainly by the liver or kidneys or both and the total clearance (Cls) is the sum of clearance by the liver and by the kidneys. For the vast majority of drugs clearance remains approximately constant irrespective of the concentration of drug in the plasma. Such drugs obey a condition known as linear or first-order kinetics and, for these drugs, it is possible to predict how, given a particular dose schedule, plasma concentrations will vary over time. RELATIONSHIP BETWEEN DRUG DOSE AND PLASMA CONCENTRATION For drugs obeying first-order kinetics, and if it is assumed that the drug is contained within a single compartment, then there is a simple relationship between drug dose, Vd, Cls and plasma concentrations of the drug over time. When a single dose is given, plasma concentrations rise to a maximum (Cmax) dependent on the dose of drug and volume of distribution; thereafter plasma concentrations fall over time.

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The time taken for the concentration to fall by 50% is constant (given the provision of one-compartment first-order kinetics) and is called the half-life (t1/2) of the drug; Usually drugs are given at repeated intervals. In this case plasma concentrations rise over the course of approximately three half-lives to fluctuate around an average steady state concentration determined by the daily dose (D) and the clearance of the drug. Fluctuation of the plasma concentration around this level is determined by dose interval and t1/2. The shorter the dose interval in comparison to t1/2, the smaller the fluctuation (which may be quantified by the peak/trough ratio). Depending upon the clinical urgency of a situation it may not be expedient to wait three half-lives to reach the desired therapeutic concentration at steady state. In such cases an initial loading dose can be given followed by a maintenance dose. The size of the loading dose is determined by Vd whereas that of the maintenance dose is determined by Cls. These considerations are strictly true only for drugs distributed within a single compartment which obey first-order kinetics. In reality, most drugs are distributed across many compartments with different equilibrium constants. Despite this, the simple single-compartment model provides a useful description for most drugs. There are, however, important exceptions. For those drugs for which Cls is not constant, such as phenytoin and alcohol, which exhibit saturation kinetics, the relationship between dose and plasma concentration is more complex. In particular, the average steady state concentration is not proportional to daily dose and a small increase in dose per unit time can lead to a large increase in plasma concentrations. PHYSIOLOGICAL CHANGES IN PREGNANCY Physiological changes in pregnancy, beginning during the first trimester, and most marked during the third trimester, alter the absorption, distribution and clearance of drugs. In addition, most drugs gain access to the feto-placental unit. These changes are detailed below before considering specific effects for individual classes of drugs.

Absorption Gastric emptying and small intestine motility are reduced in pregnancy due to elevation of progesterone. This may increase Tmax and reduce Cmax, although effects on total bioavailability may be relatively minor. An increase in gastric pH, due to a reduction in secretion and an increase in mucus production, may increase the ionization of weak acids, tending to reduce their absorption more than that of weak bases. Such effects are unlikely to be important during repeated dosing.

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They may, however, reduce the effie cacy of a single dose of an oral drug such as an analgesic or anti-emetic for which Tmax and Cmax are important. A more practical problem for drug absorption is the nausea and vomiting associated with pregnancy. If nausea is reduced in the evening its effects on absorption can be minimized by deferring dosing until the evening (in the case of once-daily dosing). Absorption of drugs administered by inhalation may be enhanced due to increased cardiac output and tidal volume increasing alveolar uptake. Distribution During pregnancy there is an expansion of intravascular (plasma volume) and extra vascular (breasts, uterus, peripheral oedema) water content. Thus, total body water increases by up to 8 litres, creating a larger space within which hydrophilic drugs may distribute. As a result of this apparent dilution, Cmax of many hydrophilic drugs is reduced, although the clinical effect of this is compensated by changes in proteinbinding. Total plasma concentration of albumin-bound drugs decreases as a result of haemodilution and the subsequent fall in plasma albumin concentration. In addition, steroid and placental hormones displace drugs from their protein-binding sites. There is thus the possibility of a rise in free (active) drug concentration of agents that are normally albumin-bound. This would be expected to produce an increased drug effect. However, unbound drug is distributed, metabolized and excreted, and so free concentration of drug is little influenced. These changes in protein binding are of clinical importance when monitoring plasma concentrations of drugs, for example, phenytoin, as most laboratories report total (rather than free) drug concentration. Body fat increases by approximately 4 kg, creating a larger volume of distribution for lipophilic drugs but this has little practical importance.

Metabolism Some enzymes of the hepatic cytochrome P-450 system are induced by oestrogen/ progesterone, resulting in a higher rate of metabolism (and hence elimination) of drugs, for example, phenytoin, whereas other isoenzymes are competitively inhibited by progesterone and oestradiol, leading to impaired elimination, for example, theophylline. Clearance of drugs, such as rifampicin, that are secreted via the biliary system, may be attenuated due to the cholestatic property of oestrogen. Some extra-hepatic enzymes, such cholinesterase, have diminished activity during pregnancy. Elimination
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Renal blood flow is increased by 60-80% during pregnancy, and glomerular filtration rate rises by 50%, leading to enhanced elimination of drugs that are normally excreted unchanged for example, penicillin and digoxin. This leads to slightly lower steady-state drug concentrations, although this rarely necessitates increasing the dosage. Feto-placental unit Drug transfer occurs mainly via diffusion across the placenta, thus favouring the movement of lipophilic agents, and the rate-limiting step is placental blood flow. Protein-bound drugs, and drugs of large molecular weight, for example heparin and insulin, do not cross the placenta. Both the immature fetal liver and the placenta can metabolize drugs. Immature phase I and phase II metabolism can occur in the fetus 8 weeks postconception. However, metabolic enzyme activity is low, and this coupled with the fact that 50% of the fetal circulation from the umbilical vein bypasses the fetal liver to the cardiac and cerebral circulations contributes to the problem of fetal drug accumulation. Another process leading to accumulation of drugs within the fetus is the phenomenon of `ion trapping'. The basis for this is the (slightly) more acidic nature of fetal plasma pH compared to maternal plasma. Weak bases, which are mainly non-ionized (lipophilic), diffuse across the placental barrier and become ionized in the more acidic fetal blood, leading to a net movement from the maternal to fetal systems. SUMMARY Changes in maternal physiology during pregnancy impact on pharmacokinetics with a tendency to reduced plasma concentrations. Definitive information from studies that could be used to formulate therapeutic guidelines for the safe use of drugs in pregnancy is, however, limited and at present there is little evidence to formulate clear-cut guidelines with respect to dosing schedules for individual drugs.

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